使用GPR119和GPR40激动剂联合激活肠道内分泌细胞可在小鼠和人类中产生协同激素分泌，这一成果由美国Kallyope公司Shirly Pinto研究组经过不懈努力而取得。相关论文发表在2025年12月2日出版的《细胞—代谢》杂志上。

该课题组人员描述了直接靶向EECs来模拟减肥手术的效果。利用先进技术全面了解EEC多样性，鉴定出既表达饱腹激素又表达靶受体的细胞，包括GPR40 （FFAR1）和GPR119。研究小组开发了这些受体的肠道靶向激动剂，K-757和K-833，并在小鼠和人类肠道中证明了协同激素分泌。这种组合在改善小鼠的葡萄糖耐量和促进体重减轻方面很有效。在1期试验中观察到的循环肠道激素水平超过了减肥手术中观察到的水平，这证明了这些化合物在减肥和血糖控制方面的进一步临床研究。

据了解，关于减肥手术减肥效果的一个主要假设是肠道肠内分泌细胞（EECs）的超生理激活，导致餐后饱腹激素水平升高，包括胰高血糖素样肽-1（GLP-1）。

附：英文原文

Title: Gut enteroendocrine cell activation using a combination of GPR119 and GPR40 agonists results in synergistic hormone secretion in mice and humans

Author: Iyassu K. Sebhat, Monika J.M. Murphy, Shuqin Zheng, Robert J. Lovelett, Maja Engelstoft, Daniel Kosinski, Xiaodong Yang, Victoria Dunn, John Whang, Maximilian G. Lombardo, Adrian Heilbut, Giuseppe Terracina, Nicole Nicholas, Molly Leitner, Matthew J. Consolati, Bryan Chan, Gregory Poterewicz, Annemarie Vance, Jiajun Liu, Ann E. Weber, Brett Lauring, Nancy Thornberry, Shirly Pinto

Issue&Volume: 2025-12-02

Abstract: A leading hypothesis for the effectiveness of bariatric surgery for weight loss is supraphysiologic activation of gut enteroendocrine cells (EECs), which results in elevated postprandial levels of satiety hormones, including glucagon-like peptide-1 (GLP-1). Here, we describe direct targeting of EECs to mimic effects of bariatric surgery. Advanced technologies were used to obtain a comprehensive understanding of EEC diversity, resulting in the identification of cells that express both satiety hormones and target receptors, including GPR40 (FFAR1) and GPR119. We developed gut-targeted agonists of these receptors, K-757 and K-833, and demonstrated synergistic hormone secretion in murine and human enteroids. The combination was efficacious in improving glucose tolerance and promoting weight loss in mice. The levels of circulating gut hormones observed in phase 1 trials exceeded levels observed in bariatric surgery, warranting further clinical investigation of these compounds for weight loss and glucose control.

DOI: 10.1016/j.cmet.2025.11.001

Source: https://www.cell.com/cell-metabolism/abstract/S1550-4131(25)00485-1